This is an outpatient clinical trial of topiramate treatment for cocaine dependence and reduction of cocaine- associated HIV risk behavior. Topiramate is of high current interest in this regard, having been identified my NIDA leadership as among only a small number of tested candidates providing a "positive signal" and warranting further clinical investigation (Vocci, 2005). Topiramate is a marketed antiepileptic that enhances the GABAergic system and antagonizes the glutamatergic system, both new targets in the search for anti- cocaine treatments. A published pilot trial has supported topiramate's efficacy, and it is especially intriguing as potentially beneficial against other disorders prevalent among drug users, such as mood, anxiety, panic disorders, PTSD, pain and cognitive dysfunction, that may contribute to drug use. Design/Methods: This is Phase II, double-blind randomized (stratified) 4 group, 2 x 2 design, evaluating topiramate versus placebo under each of two levels of cocaine-abstinence motivation -- cocaine-abstinence-contingent versus non-contingent voucher incentives. Conduct will be in a methadone maintenance context to ensure adequate retention and adherence, with participants dually dependent on opioids and cocaine. The target topiramate stabilization dose is 300 mg/day (150 mg b.i.d.), with one dose per day being observed at the clinic. The voucher-incentive manipulation provides valuable information about the role of motivation in modulating medication effects; it also provides a positive control condition to document the sensitivity of the study methods for detecting therapeutic benefit. Enrollment will be 300 patients (240 completers, 60/group). Participation will be up to 33 weeks - Baseline/Placebo-Run-in (5 weeks), Randomized Medication Treatment (20 weeks, induction, stable dosing, taper), Randomized Voucher Treatment (12 weeks, embedded in Medication period), and Therapeutic Disposition (up to 8 weeks). Data analysis focuses on the 8-week period of stable dosing and concurrent vouchers. The primary outcome variable is days abstinent from cocaine, as determined by a combination of self-report and objective confirmation by quantitative urinalysis toxicology of cocaine metabolite levels and application of the "Preston" rule for determining abstinence. Secondary outcome variables are measures of adverse behaviors and symptoms commonly co- occurring in cocaine abusers (alcohol abuse, tobacco use, depression, anxiety, PTSD, pain, neurocognitive and psychomotor performance dysfunction) that may contribute to drug use and/or detrimental effects. Significance: This randomized controlled clinical trial will provide valuable information about the actions and therapeutic effectiveness of the promising candidate anti-cocaine pharmacotherapy topiramate, and about the conditions, correlates, and modulators of any observed effectiveness. It will also provide valuable methodological information contributing to the continuing evolution of clinical trial methods for evaluating potential drug abuse treatment medications. [unreadable] [unreadable] [unreadable]